The functional heterogeneity of the vasculature contributes to the etiology of pulmonary and peripheral vascular diseases. Protein kinase C (PKC) is a pivotal regulator of vascular tone and is divided into classical PKCs (cPKC), novel PKCs (nPKCs) and a typical PKCs (aPKCs). It is generally held that activation of PKC elicits vascular smooth muscle contraction. However, our initial studies have provided compelling support for the Hypothesis that aPKC play opposite roles in regulating tone in conduit and resistance arteries, and specifically that aPKC activation supports contraction in conduit arteries whereas aPKC suppresses contraction in resistance arteries. We determine that the contractile response elicited by inhibition of aPKC in resistance arteries involves 1) activation of Rho-kinase, 2) voltage-gated and non-voltage Ca2+ entry, and 3) is dependent on the activation of both cPKC and nPKC isoforms. Our long term goals are to combine functional and molecular biology approaches to elucidate the mechanisms underlying the heterogeneous control of vascular smooth muscle by aPKC and to determine the precise role of aPKC in the heterogeneous vascular response to both physiological and pathological stimuli. The Specific Aims of this proposal are: Aim 1: To determine the degree of heterogeneity in the role of basal aPKC activity in the functional regulation of rat conduit and resistance artery tone. Aim 2: To determine the signal transduction mechanisms underlying the heterogeneous control of rat conduit and resistance artery tone by aPKC. Aim 3: To determine the degree of heterogeneity in the expression and basal activity of aPKC in rat conduit and resistance arteries. The novel studies detailed in this proposal will provide functional and molecular insights into the regulation of tone in conduit and resistance arteries of the pulmonary and peripheral vasculature. As such, these studies are likely to provide insights into the functional heterogeneity of the vasculature and may identify aPKC as a candidate mediator of vascular heterogeneity.